| Summary: | <p>Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in the young. Acute myocardial ischaemia (a sudden myocardial blood supply/demand mismatch) and pre-existing chronic ionic remodelling (which causes slowed cellular repolarisation) are acknowledged as two key contributors to lethal arrhythmias, but the assessment of these disease factors is absent from HCM clinical guidelines. Using multiscale modelling of cardiac electrophysiology, this thesis aimed to investigate the electrophysiological effects of myocardial ischaemia and ionic remodelling in HCM, to benefit arrhythmic risk predictions, the ECG diagnosis of ischaemia, and antiarrhythmic therapy.</p>
<p>Computational models of human HCM cardiomyocytes with ionic remodelling were subjected to ischaemia and action potential biomarkers were measured, then validated in vitro with human HCM patch-clamp experimental data from collaborators. Biventricular simulations with regional ischaemia, informed by clinical HCM perfusion imaging data, were used to measure independent arrhythmic risk contributions from ionic remodelling using S1-S2 pacing protocols. ECGs were further derived from ischaemic biventricular simulations, and compared to those under benign exercise effects, to investigate HCM-specific stress ECG diagnostic markers of ischaemia. Finally, arrhythmic risk was measured in HCM biventricular simulations under the pharmacologic effects of ranolazine.</p>
<p>HCM cardiomyocytes had enhanced sensitivity to ischaemia, where the presence of ionic remodelling increased arrhythmic risk in ischaemic simulations, particularly for transmural insults. This enhanced ischaemic cellular response manifested as pseudonormalisation of ECG repolarisation abnormalities, but benign exercise effects also contributed, possibly mimicking signs of ischaemia on the ECG and complicating its diagnosis. Finally, the antiarrhythmic efficacy and safety of ranolazine was dependent on the severity of ionic remodelling and may be predicted using the ECG, with optimal effects in cases of moderate ionic remodelling, but potential proarrhythmic effects in severe-extreme cases.</p>
<p>Ionic remodelling in HCM makes independent contributions to ischaemic arrhythmic risk, facilitates HCM-specific manifestations of ischaemia on the ECG, and may be a therapeutic target for the amelioration of arrhythmias with ranolazine.</p>
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